Field of the Invention
The invention relates to the C5aR2 receptor and ligands thereof.
Related Art
The complement cascade is an ancient part of our innate immune system that can be activated following tissue injury/damage and in response to foreign bodies1. Following activation of the cascade the complement peptides C3a, C4a and C5a are generated prior to the termination of the cascade with the formation of the membrane attack complex1. C5a is a potent immunomodulator, but also has emerging roles outside of immunity during embryonic development2. Its production is tightly controlled in order to produce a rapid response to tissue injury/pathogens yet protect against unwanted activity on host tissue1, 3, 4. The disruption of this control can lead to the overproduction of C5a, which can lead to an uncontrolled inflammatory response. C5a has been associated with a number of autoimmune, inflammatory and neurodegenerative disorders5, 6 although, interestingly, the overproduction of C5a can lead to a down regulation of the immune response in some leukocytes, but have the opposite effect on other cell types7, 8.
Two receptors have been shown to bind C5a: the C5a receptor 1 (C5a1, CD88, or C5aR1) and the C5a receptor 2 (C5a2, C5L2, or C5aR2)9, 10. C5a1 and C5a2 receptors are known to have important functions in many inflammatory conditions3. C5a1 is a classical G protein-coupled receptor (GPCR) and activation following C5a binding leads to predominantly Gαi activation which in turn activates multiple intracellular signalling pathways (including ERK, Akt, MAPK and PI3K) and β-arrestin recruitment for receptor desensitisation, recycling and perhaps also G-protein independent signalling1, 3. C5a2 is a seven transmembrane domain receptor but is not coupled to G-proteins, partly due to key amino acid changes in the critical cytosolic DRY and NPXXY motifs where G-proteins have been shown to bind11. However, C5a2 has been shown to bind to β-arrestins12, 13. C5a2 was originally thought to be a simple recycling decoy receptor, similar to the chemokine receptor D614. This assumption is no longer accepted as C5a2 has now been shown to have both pro- and anti-inflammatory activities, and also to have its own functional role, which is likely to be regulated through β-arrestin recruitment and signalling15, 16. We have recently published a model that potentially explains the contradictory role of C5a2 having both pro- and anti-inflammatory activities, through the modulation of C5a induced C5a1 signalling via C5aR2 mediated β-arrestin recruitment17.
Two inflammatory conditions that are strongly associated with the dysregulation of C5a are sepsis and inflammatory bowel diseases (IBD)7, 18. The detrimental effects of C5a in sepsis have been well studied and include paralysis of neutrophil immune function, promotion of septic cardiomyopathy, is a driver of apoptosis of adrenal medullar cells and thymocytes and consumptive coagulopathy which can all lead to multi-organ failure5, 19. Using the caecal ligation and puncture (CLP) model of high grade sepsis in mice it was shown that C5a1 and C5a2 null animals had an 85% and 80% survival rate, respectively at day 3 compared to 0% in normal mice20. This data suggests that there is a cooperative interaction between C5a1 and C5a2 during the development of sepsis. Subsequently, this led to studies that showed that blocking of C5a or of both C5a receptors to be some of the most effective therapeutic treatment options for sepsis21. IBD is a chronic inflammatory condition of the gastrointestinal tract that is characterised by a relapsing/remitting inflammation caused by dysfunctioning mucosal T cells and irregular cytokine production that leads to damage to the mucosal lining of the intestine22. Studies using C5a1 knockout mice have shown that C5a1 has detrimental effects in acute colitis induced by dextran sodium sulphate (DSS)23, which suggested that, a C5a1 antagonist maybe an effective therapeutic option for IBD18. The pro-inflammatory cytokine IL-6 has been shown to play a key role in both of these conditions and is also involved in regulating the expression of C5a1 during sepsis24, 25.